Downloaded from http://cshperspectives.cshlp.org/ on September 26, 2021 - Published by Cold Spring Harbor Laboratory Press Signaling in Lymphocyte Activation Doreen Cantrell College of Life Sciences, Wellcome Trust Biocentre, University of Dundee, Dundee DD1 5EH, Scotland, United Kingdom Correspondence: [email protected] SUMMARY The fate of T and B lymphocytes, the key cells that direct the adaptive immune response, is regulated by a diverse network of signal transduction pathways. The T- and B-cell antigen receptors are coupled to intracellular tyrosine kinases and adaptor molecules to control the metabolism of inositol phospholipids and calcium release. The production of inositol poly- phosphates and lipid second messengers directs the activity of downstream guanine-nucleo- tide-binding proteins and protein and lipid kinases/phosphatases that control lymphocyte transcriptional and metabolic programs. Lymphocyte activation is modulated by costimulatory molecules and cytokines that elicit intracellular signaling that is integrated with the antigen- receptor-controlled pathways. Outline 1 Introduction 9 Ras signaling and lymphocytes 2 Antigen-receptor structure and function 10 Costimulatory molecules, cytokines, and lymphocyte activation 3 Immunoreceptor tyrosine-based activation motifs 11 Cytokine signaling in lymphocytes 4 Adaptor molecules for antigen receptors 12 PI3K-mediated signaling in lymphocytes 5 Calcium and diacylglycerol signaling 13 Inhibitory signals and lymphocyte activation 6 Downstream from calcium signaling 14 Concluding remarks in lymphocytes References 7 Diacylglycerol signaling in lymphocytes 8 PKC and lymphocytes Editors: Lewis Cantley, Tony Hunter, Richard Sever, and Jeremy Thorner Additional Perspectives on Signal Transduction available at www.cshperspectives.org Copyright # 2015 Cold Spring Harbor Laboratory Press; all rights reserved; doi: 10.1101/cshperspect.a018788 Cite this article as Cold Spring Harb Perspect Biol 2015;7:a018788 1 Downloaded from http://cshperspectives.cshlp.org/ on September 26, 2021 - Published by Cold Spring Harbor Laboratory Press D. Cantrell 1 INTRODUCTION and guanine-nucleotide-binding proteins that control lym- phocyte proliferation, differentiation, and effector func- The adaptive immune response is directed by B and T lym- tion. Below, I outline both the unique and the conserved phocytes. These cells express specific receptors that recog- aspects of signaling in lymphocytes, focusing on signaling nize pathogen-derived antigens: the B-cell antigen receptor pathways controlled by antigen receptors and how these (BCR) and the T-cell antigen receptor (TCR), respectively. responses are subsequently shaped and modulated by cyto- B lymphocytes have two principal roles: to produce and kines and chemokines. secrete specific antibodies/immunoglobulins, and to func- tion as antigen-presenting cells (APCs). T cells have multi- 2 ANTIGEN-RECEPTOR STRUCTURE AND ple roles in adaptive immune responses. In this context, FUNCTION peripheral T cells can be subdivided on the basis of whether they express CD8 or CD4, receptors that recognize class The TCR and BCR are multiprotein complexes comprising I and class II major histocompatibility complex (MHC) subunits containing highly variable antigen-binding re- + molecules, respectively. CD8 T cells differentiate to cy- gions linked noncovalently to invariant signal transduction tolytic effectors that directly kill virus- or bacteria-infected subunits. In both cases, rearrangements of the DNA se- + cells. CD4 T cells are referred to as “helper” T cells because quences that encode the antigen-binding region create a they produce regulatory cytokines and chemokines that diversity in antigen-receptor structures. A key feature of mediate autocrine or paracrine control of T-cell differenti- T- and B-cell populations is that each individual lympho- ation and/or regulate the differentiation of B cells and/or cyte will express multiple copies of a unique antigen re- direct the activity of macrophages and neutrophils (O’Shea ceptor with a single antigen specificity (defined by three and Paul 2010). At least five major subpopulations of complementarity-determining regions [CDRs]). It is the + mature CD4 cells exist with distinct functions that are selectivityof antigen receptors that underpins immune spe- tailored to deal with different pathogens. Th1 cells, charac- cificity by ensuring that only those lymphocytes that recog- terized by interferon (IFN)g production; Th2 cells, charac- nize a specific pathogen are activated by it. terized by interleukin 4 (IL4) and IL13 production; Th17 The BCR is composed of a highly variable membrane- cells, which produce the proinflammatory cytokines IL17 boundimmunoglobulinofeither theIgMorIgD subclassin and IL22; regulatory T (Treg) cells that function to restrain a complex with the invariant also known as Iga and Igb autoimmunity and strong inflammatory responses; and (CD79a and CD79b) heterodimer (Tolar et al. 2009). Im- + follicular helper T (Tfh) cells, a class of effector CD4 T munoglobulin subunits are highly variable because the cellsthat regulate the development of antigen-specific B-cell genes that encode these proteins undergo rearrangements immunity. and somatic hypermutation during B-cell development, The paradigm of the adaptive immune response is that a which produces a high degree of protein diversity (≥1011 primary response to an antigen causes clonal expansion of different receptors) (Schatz and Ji 2011). antigen-reactive Tor B cells and produces a large number of The TCR is also characterized by highly variable anti- effector lymphocytes that cause clearance of the pathogen. gen-binding subunits, either an ab or a gd dimer (Davis Once the pathogen is cleared there is a contraction phase of 2004; Krogsgaard and Davis 2005; Xiong and Raulet 2007). the immune response characterized by loss of effector lym- These are coupled to the invariant CD3 subunits g1, d1, phocytes and the emergence of long-lived memory cells and zz, which are essential for trafficking and stabilityof the capable of mounting rapid secondary responses to reinfec- gd and ab subunits at the plasma membrane. CD3 anti- tion with the original pathogen. gens also transmit signals into the cell across the plasma The proliferation and differentiation of mature lym- membrane. Like the BCR immunoglobulin sequences, the phocytes in adaptive immune responses are directed by TCR-ab or gd dimers are highly variable because the genes antigen receptors, costimulatory molecules, adhesion mol- that encode them undergo rearrangements (but not hyper- ecules, cytokines, and chemokines. These extrinsic stimuli mutation) during their development. Indeed, there is po- are coupled to a diverse network of signal transduction tential for the production of 1018 different TCR-ab pathways that control the transcriptional and metabolic receptor complexes. This is compared with to a minimal programs that determine lymphocyte function. At the estimate of 1011 BCR complexes. The salient feature is that core of lymphocyte signal transduction is the regulated each T cell only expresses an ab or a gd receptor complex metabolism of inositol phospholipids and the resultant with a single specificity. production of inositol polyphosphates and lipids such as T cells that express TCR-gd complexes are found pre- polyunsaturated diacylglycerols (DAGs). These second dominantly at epithelial barriers (e.g., in the skin and gut messengers direct the activity of protein and lipid kinases epithelia). The ligands for TCR-gd complexes are not well 2 Cite this article as Cold Spring Harb Perspect Biol 2015;7:a018788 Downloaded from http://cshperspectives.cshlp.org/ on September 26, 2021 - Published by Cold Spring Harbor Laboratory Press Signaling in Lymphocyte Activation defined but can be bacterial phosphoantigens, alkylamines, mast cells Syk is recruited (Chu et al. 1998). Zap-70 and Syk and aminobisphosphonates (Hayday 2009). T cells that ex- contain tandem SH2 domains that bind with high affinity press TCR-ab complexes typically recirculate between the to the doubly phosphorylated ITAM (Chu et al. 1998). The blood, secondary lymphoid organs (spleen and lymph activation of Zap-70 or Syk is initiated by binding to phos- nodes), and the lymphatic system. The ligands for TCR-ab phorylated ITAMs. This is proposed to release Syk/Zap-70 complexes are not antigens per se but rather pathogen- (or from an autoinhibited conformation and expose regulatory transplantation-antigen)-derived peptides bound to MHC tyrosine residues for phosphorylation by Src-family kinases molecules, a group of molecules that display the short, ap- (Au-Yeung et al. 2009). The phosphorylation of tyrosine proximately nine-residue peptides on the surface of APCs. residues in the activation loop in the Zap-70/Syk catalytic TCR-ab-expressing T cells are thus not triggered by soluble domain, as well as two residues in the adjacent linker region, pathogen-derived peptides but only by peptide-MHC com- then further stimulates their catalytic activity. Antigen-re- plexes on the surface of dendriticcells, B cells, and othercells ceptor control of Syk-family tyrosine kinases is fundamen- that can function as APCs (Krogsgaard and Davis 2005). tal for lymphocyte activation and underpins the ability of antigen receptors to transduce signals from pathogen-de- rived antigens to the interior of lymphocytes (Mocsai et al. 3 IMMUNORECEPTOR TYROSINE-BASED 2010; Wang et al. 2010). ACTIVATION MOTIFS How the Src-family kinases such as